Dual TCR-α expression on mucosal-associated invariant T cells as a potential confounder of TCR interpretation

Suliman, Sara, Kjer-Nielsen, Lars, Iwany, Sarah K., Lopez Tamara, Kattya, Loh, Liyen, Grzelak, Ludivine, Kedzierska, Katherine, Ocampo, Tonatiuh A., Corbett, Alexandra J., McCluskey, James, Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, León, Segundo R., Calderon, Roger, Lecca-Garcia, Leonid, Murray, Megan B., Moody, D. Branch and Van Rhijn, Ildiko 2022. Dual TCR-α expression on mucosal-associated invariant T cells as a potential confounder of TCR interpretation. Journal of Immunology 208 (6) , pp. 1389-1395. 10.4049/jimmunol.2100275

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Abstract

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that are highly abundant in human blood and tissues. Most MAIT cells have an invariant TCRα-chain that uses T cell receptor α-variable 1-2 (TRAV1-2) joined to TRAJ33/20/12 and recognizes metabolites from bacterial riboflavin synthesis bound to the Ag-presenting molecule MHC class I related (MR1). Our attempts to identify alternative MR1-presented Ags led to the discovery of rare MR1-restricted T cells with non–TRAV1-2 TCRs. Because altered Ag specificity likely alters affinity for the most potent known Ag, 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU), we performed bulk TCRα- and TCRβ-chain sequencing and single-cell–based paired TCR sequencing on T cells that bound the MR1-5-OP-RU tetramer with differing intensities. Bulk sequencing showed that use of V genes other than TRAV1-2 was enriched among MR1-5-OP-RU tetramerlow cells. Although we initially interpreted these as diverse MR1-restricted TCRs, single-cell TCR sequencing revealed that cells expressing atypical TCRα-chains also coexpressed an invariant MAIT TCRα-chain. Transfection of each non–TRAV1-2 TCRα-chain with the TCRβ-chain from the same cell demonstrated that the non–TRAV1-2 TCR did not bind the MR1-5-OP-RU tetramer. Thus, dual TCRα-chain expression in human T cells and competition for the endogenous β-chain explains the existence of some MR1-5-OP-RU tetramerlow T cells. The discovery of simultaneous expression of canonical and noncanonical TCRs on the same T cell means that claims of roles for non–TRAV1-2 TCR in MR1 response must be validated by TCR transfer-based confirmation of Ag specificity.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Medicine
Publisher:	American Association of Immunologists
ISSN:	0022-1767
Date of Acceptance:	12 January 2022
Last Modified:	10 Nov 2022 11:24
URI:	https://orca.cardiff.ac.uk/id/eprint/150336

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